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The material extrusion of plastics has matured into a lucrative and flexible alternative to conventional manufacturing. A major downside of this process is the missing quality assurance caused by the influence of process parameters on part quality. Such parameters—e.g., infill density and print speed—are selected prior to manufacturing. As a result, the achieved part quality is mostly unknown, limiting the use of material extrusion and leading to increased material costs and print times. A promising approach to overcome this drawback are prediction models, especially methods of machine learning. Yet, a methodology that enables their integration in the manufacturing process is lacking. This paper provides a methodology based on a lookup approach and calculated safety factors. The methodology is tested and subsequently applied to two exemplary use cases. The result empowers users and researchers with a methodology to use prediction models for quality assurance in their company environment. On the other hand, future improvements and new research results can be integrated into the methodology to verify its applicability in practice.

A stainless precipitation hardening steel has been qualified for powder bed fusion of metals using a laser beam. The mechanical and microstructural properties of additively manufactured samples have been thoroughly investigated and compared to samples of the very same material made by means of ingot casting. Additive manufacturing is feasible and can deliver superior mechanical properties. Additionally, the surface quality will be improved by means of wet abrasive jet machining, and its impact on the residual stresses has been shown.

The importance of powder-bed fusion of metals using a laser beam (PBF-LB/M) in industry and research is still gaining. Current developments are aimed at various aspects to increase the performance of the PBF-LB/M process and the manufactured parts. For example, systems with multiple lasers are being developed, and new alloys, new exposure strategies as well as the influence of the process parameters on the part properties are being investigated. This work analyses the influence of a vibrating build platform on the density and hardness of parts manufactured by PBF-LB/M. It is shown that a vibrating build platform influences the part density, especially for process parameters, which typically lead to lower relative part densities. For all investigated samples, the hardness increased with the use of a vibrating build platform.

Users of material extrusion printers are faced with a wide range of prices. It is unknown which printer price can achieve the required part quality. However, the price and the resulting quality of a printer are decisive factors for the process, especially at small- and medium-sized companies. This study investigated the correlation between the printer price and part quality based on dimensional accuracy, surface quality, strength, and visual appearance. In this paper, 14 printers with different prices were examined. The relationship of printer price and part defects, elongation at break, and the accuracy of roundings could be identified (the regressions achieved a p-value under 0.5 and an R2 over 0.4). A relationship with surface roughness, tensile strength, or other dimensional accuracy characteristics could not be found (the regressions achieved an R2 under 0.4 or anomalies could be detected in the regression analysis). In the performed investigations, more-expensive printers were not necessarily associated with an improvement in these quality characteristics. No relationship between the printer price and the standard deviation, e.g., less variation in part quality, could be identified. This paper provides valuable insights into the relationship of part quality and printer price. The performed research improved upon the existing literature in terms of the number of investigated printers, the observed price range, and the number of tested quality characteristics. The results and approach of this paper will help users select an appropriate printer, and the findings can be used in the sourcing and technology selection phases.

Assessing social acceptability is vital when designing body-worn mobile devices. Previous research found evidence that using stereotyping content model (SCM) mobile devices can systematically predict ratings of the warmth and competence of their wearers. However, it is currently unknown if other contextual dimensions of mobile device usage can also systematically affect those ratings. In two studies, we investigate if and how shape and body location of a body-worn mobile device as well as the activity in which the device is being used can systematically influence stereotypical ratings. Our results suggest that this is evident in some but not all cases. We conclude that people further differentiate between the placement of the device, particularly devices in the user’s hand, and during an activity in which the device can contextually be misused. This indicates that users further differentiate the context and that more contexual information is helpful while operationalizing the SCM as a measure for social acceptability.

The modification of metal alloy powders by coating with nanoparticles offers the possibility to improve additive manufacturing processes, in particular the powder bed fusion of metals with laser beams (PBF/LB-M), from the material side of view. Subsequently, component qualities including mechanical properties and microstructural characteristics could be improved. Furthermore, the modification enables improved energy utilization due to an increase in laser absorption. In this work three commercial additive manufacturing powders, namely stainless steel (1.4404), tool steel (1.2709), and aluminum alloy (3.2381) were coated with three different nanoparticles (Silicon carbide (SiC), few layer graphene (FLG), and iron oxide black (IOB) to increase the laser light absorption in the PBF/LB/M process, mechanical properties, and flowability of the powders. The coating was conducted within a fluidized bed system, resulting in homogeneous coatings. This study demonstrates, that well scalable processes i.e. stirred media milling and fluidized bed coating have the potential to improve the commercial AM powders regarding their bulk density, flowability, and energy absorption, which is a crucial step towards an improvement in the efficiency of the whole PBF process. Overall important information and relations were gathered to transfer them to the real powder deposition process in future work.

One of the AM processes for direct manufacturing of metallic components is powder bed fusion of metals using a laser beam system (PBF-LB/M), in which metallic powders are molten and solidified in a layer upon layer manner by a focused laser beam. In recent years, the focus has initially been on increasing the efficiency of the systems itself. However, the modification of standard AM metal alloys using nanoparticles offers the possibility to improve the PBF-LB/M-process concerning its process efficiency and actual densification and thermal conductivity. In this work, a methodology for an in-situ investigation of the thermal conductivity as well as the reflectance behavior of metallic powder materials during the PBF-LB/M-process is established. The powder material stainless steel 1.4404 was coated with different nanoparticles (few-layer graphene (FLG), silicon carbide (SiC)) and processed in a standardized build process. As a result, the reflectance rate of all modified materials could be increased. Besides, the thermal conductivity of the material is attested to be a decisive and influencing factor for the quality of the final component. Thus, an improved relative density was achieved using the FLG/1.4404 and SiC/1.4404 (1 vol%) due to the increased thermal conductivity of the material. Also significant defects in the cross section were visible at SiC/1.4404 (4 vol%).

Powder bed fusion of metals using a laser beam system (PBF-LB/M) of highly complex and filigree parts made of tool steels is becoming more important for many industrial applications and scientific investigations. To achieve high density and sufficient chemical homogeneity, pre-alloyed gas-atomized spherical powder feedstock is used. For high-performance materials such as tool steels, the number of commercially available starting powders is limited due to the susceptibility to crack formation in carbon-bearing steels. Furthermore, scientific alloy development in combination with gas-atomization is a cost-intensive process which requires high experimental effort. To overcome these drawbacks, this investigation describes the adaption of a hot work tool steel for crack-free PBF-LB/M-fabrication without any preheating as well as an alternative alloying strategy which implies the individual admixing of low-cost aspherical elemental powders and ferroalloy particles with gas-atomized pure iron powder. It is shown that the PBF-LB/M-fabrication of this powder mixture is technically feasible, even though the partly irregular-shaped powder particles reduce the flowability and the laser reflectance compared to a gas-atomized reference powder. Moreover, some high-melting alloying ingredients of the admixed powder remain unmolten within the microstructure. To analyze the laser energy input in detail, the second part of the investigation focuses on the characterization of the individual laser light reflectance of the admixed alloy, the gas-atomized reference powder and the individual alloying elements and ferroalloys.

Human CYP3A enzymes (including CYP3A4 and CYP4A5) metabolize about 40% of all drugs and numerous other environmental and endogenous substances. CYP3A activity is highly variable within and between humans. As a consequence, therapy with standard doses often results in too low or too high blood and tissue concentrations resulting in therapeutic failure or dose-related adverse reactions. It is an unanswered question how much of the big interindividual variation in CYP3A activity is caused by genetic or by environmental factors. This question can be answered by the twin study approach. Using midazolam as CYP3A probe drug, we studied 43 monozygotic and 14 dizygotic twins and measured midazolam and its metabolite 1-OH-midazolam. In addition, endogenous biomarkers of CYP3A activity, 4ß-OH-cholesterol and 6ß-OH-cortisol, were analyzed. Additive genetic effects accounted for only 15% of the variation in midazolam AUC, whereas 48% was attributed to common environmental factors. In contrast, 73, 56, and 31% of 1-OH-midazolam, 4ß-OH-cholesterol and 6ß-OH-cortisol variation was due to genetic effects. There was a low phenotypic correlation between the four CYP3A biomarkers. Only between midazolam and its 1-OH-metabolite, and between midazolam and 6ß-OH-cortisol we found significant bivariate genetic correlations. Midazolam AUC differed depending on the CYP3A4∗22 variant (p = 0.001) whereas plasma 4ß-OH-cholesterol was significantly lower in homozygous carriers of CYP3A5∗3 (p = 0.02). Apparently, non-genomic factors played a dominant role in the inter-individual variation of the CYP3A probe drug midazolam. A small intra-individual pharmacokinetic variation after repeated administration of midazolam was rated earlier as indication of high heritability of CYP3A activity, but according to present data that could also largely be due to constant environmental factors and/or heritability of liver blood flow. The higher heritabilities of 4ß-OH-cholesterol and of 1-OH-midazolam may deserve further research on the underlying factors beyond CYP3A genes.Clinical Trial Registration:ClinicalTrials.gov: NCT01845194 and EUDRA-CT: 2008-006223-31.

Abstract Background Selection for a certain trait in microbes depends on the genetic background of the strain and the selection pressure of the environmental conditions acting on the cells. In contrast to the sessile state in the biofilm, various bacterial cells employ flagellum-dependent motility under planktonic conditions suggesting that the two phenotypes are mutually exclusive. However, flagellum dependent motility facilitates the prompt establishment of floating biofilms on the air-medium interface, called pellicles. Previously, pellicles of B. subtilis were shown to be preferably established by motile cells, causing a reduced fitness of non-motile derivatives in the presence of the wild type strain. Results Here, we show that lack of active flagella promotes the evolution of matrix overproducers that can be distinguished by the characteristic wrinkled colony morphotype. The wrinkly phenotype is associated with amino acid substitutions in the master repressor of biofilm-related genes, SinR. By analyzing one of the mutations, we show that it alters the tetramerization and DNA binding properties of SinR, allowing an increased expression of the operon responsible for exopolysaccharide production. Finally, we demonstrate that the wrinkly phenotype is advantageous when cells lack flagella, but not in the wild type background. Conclusions Our experiments suggest that loss of function phenotypes could expose rapid evolutionary adaptation in bacterial biofilms that is otherwise not evident in the wild type strains.

In recent years, the application field of laser powder bed fusion of metals and polymers extends through an increasing variability of powder compositions in the market. New powder formulations such as nanoparticle (NP) additivated powder feedstocks are available today. Interestingly, they behave differently along with the entire laser powder bed fusion (PBF-LB) process chain, from flowability over absorbance and microstructure formation to processability and final part properties. Recent studies show that supporting NPs on metal and polymer powder feedstocks enhances processability, avoids crack formation, refines grain size, increases functionality, and improves as-built part properties. Although several inter-laboratory studies (ILSs) on metal and polymer PBF-LB exist, they mainly focus on mechanical properties and primarily ignore nano-additivated feedstocks or standardized assessment of powder feedstock properties. However, those studies must obtain reliable data to validate each property metric’s repeatability and reproducibility limits related to the PBF-LB process chain. We herein propose the design of a large-scale ILS to quantify the effect of nanoparticle additivation on powder characteristics, process behavior, microstructure, and part properties in PBF-LB. Besides the work and sample flow to organize the ILS, the test methods to measure the NP-additivated metal and polymer powder feedstock properties and resulting part properties are defined. A research data management (RDM) plan is designed to extract scientific results from the vast amount of material, process, and part data. The RDM focuses not only on the repeatability and reproducibility of a metric but also on the FAIR principle to include findable, accessible, interoperable, and reusable data/meta-data in additive manufacturing. The proposed ILS design gives access to principal component analysis (PCA) to compute the correlations between the material–process–microstructure–part properties.

Research and development in the field of metal-based additive manufacturing are advancing steadily every year. In order to increase the efficiency of powder bed fusion of metals using a laser beam system (PBF LB/M), machine manufacturers have implemented extensive optimizations with regard to the laser systems and build volumes. However, the optimization of metallic powder materials using nanoparticle additives enables an additional improvement of the laser–material interaction. In this work, tool steel 1.2709 powder was coated with silicon carbide (SiC), few-layer graphene (FLG), and iron oxide black (IOB) on a nanometer scale. Subsequently, the feedstock material and the modified powder materials were analyzed concerning the reflectance of the laser radiation and processed by PBF-LB/M in a systematic and consistent procedure to evaluate the impact of the nano-additivation on the process efficiency and mechanical properties. As a result, an increased build rate is achieved, exhibiting a relative density of 99.9% for FLG/1.2709 due to a decreased reflectance of this modified powder material. Furthermore, FLG/1.2709 provides hardness values after precipitation hardening with only aging comparable to the original 1.2709 material and is higher than the SiC- and IOB-coated material. Additionally, the IOB coating tends to promote oxide-formation and lack-of-fusion defects.

Abstract Background Efflux transporters like MDR1 and MRP2 may modulate the pharmacokinetics of about 50 % of all drugs. It is currently unknown how much of the variation in the activities of important drug membrane transporters like MDR1 or MRP2 is determined by genetic or by environmental factors. In this study we assessed the heritability of the pharmacokinetics of talinolol as a putative probe drug for MDR1 and possibly other membrane transporters. Methods Talinolol pharmacokinetics were investigated in a repeated dose study in 42 monozygotic and 13 same-sex dizygotic twin pairs. The oral clearance of talinolol was predefined as the primary parameter. Heritability was analyzed by structural equation modeling and by within- and between-subject variance and talinolol clearance was correlated with polymorphisms in MDR1, MRP2, BCRP, MDR5, OATP1B1, and OCT1. Results Talinolol clearance varied approximately ninefold in the studied sample of healthy volunteers. The correlation of clearances between siblings was not significantly different for the monozygotic and dizygotic pairs. All data analyses consistently showed that variation of talinolol pharmacokinetics was mainly determined by environmental effects. Structural equation modeling attributed 53.5 % of the variation of oral clearance to common environmental effects influencing both siblings to the same extent and 46.5 % to unique environmental effects randomly affecting individual subjects. Talinolol pharmacokinetics were significantly dependent on sex, body mass index, total protein consumption, and vegetable consumption. Conclusions The twin study revealed that environmental factors explained much more of the variation in pharmacokinetics of talinolol than genetic factors. Trial registration European clinical trials database number: EUDRA-CT 2008-006223-31. Registered 26 September 2008. ClinicalTrials.gov number: NCT01845194 .

In this paper, laser beam melting technology is applied to the manufacture of defined porous metal structures using the exposure strategies of the machine manufacturer. It turns out that specific filter characteristics such as density, permeability, pore size, porosity, and shear strength are comparable to conventionally-made porosities [1]. To overcome some restrictions imposed by the default settings of the machine manufacturer, and to manufacture ultra-lightweight products, our own investigations such as direct slicing lead to an alternative exposure strategy for the laser. Here unique exposure lines, with their corresponding start and end points, are individually designed according to their practical needs. Even though this procedure is very complex and time-consuming, it leads to new possibilities for the perfusion of liquid or gaseous fluids that run through metal walls. In summary, the adjustment of the functional porosity of laser beam melted parts made of metal material is the focus of this investigation; and with it, the variation and determination of the proper process parameters is essential. With the easily adjustable porosities and pore sizes that are investigated, combined with the geometric freedom of laser beam melting, very complex elements can be integrated into one part; and this also leads to new fields of application.

Objective: To develop a user friendly system (S.T.O.N.E. Score) to quantify and describe stone characteristics provided by computed axial tomography scan to predict ureteroscopy outcomes and to evaluate the characteristics that are thought to affect stone free rates. Materials and Methods: The S.T.O.N.E. score consists of 5 stone characteristics: (S)ize, (T)opography (location of stone), (O)bstruction, (N)umber of stones present, and (E)valuation of Hounsfield Units. Each component is scored on a 1-3 point scale. The S.T.O.N.E. Score was applied to 200 rigid and flexible ureteroscopies performed at our institution. A logistic model was applied to evaluate our data for stone free rates (SFR). Results: SFR were found to be correlated to S.T.O.N.E. Score. As S.T.O.N.E. Score increased, the SFR decreased with a logical regression trend (p < 0.001). The logistic model found was SFR=1/(1+e^(-z)), where z=7.02-0.57*Score with an area under the curve of 0.764. A S.T.O.N.E. Score ≤ 9 points obtains stone free rates > 90% and typically falls off by 10% per point thereafter. Conclusions: The S.T.O.N.E. Score is a novel assessment tool to predict SFR in patients who require URS for the surgical therapy of ureteral and renal stone disease. The features of S.T.O.N.E. are relevant in predicting SFR with URS. Size, location, and degree of hydronephrosis were statistically significant factors in multivariate analysis. The S.T.O.N.E. Score establishes the framework for future analysis of the treatment of urolithiasis.

Purpose The purpose of this study is to determine if body mass index (BMI) and stone skin distance (SSD) affect stone free rate (SFR) in obese and morbid obese patients who underwent flexible URS for proximal ureteral or renal stones < 20 mm. Materials and Methods A retrospective chart review was performed of consecutive patients that underwent flexible URS. Inclusion criteria were: proximal ureteral stones and renal stones less than 20 mm in the preoperative computed tomography (CT). SFR were then compared according to SSD and BMI. Results A total of 153 patients were eligible for this analysis, 49 (32.02%) with SSD < 10 cm and 104 (67.97%) with SSD ≥ 10 cm. The mean stone size was 10.5 ± 6.4 mm. The overall SFR in our study was 82.4%. The SFR for the SSD < 10 and ≥ 10 were 79.6% and 83.7% respectively (p = 0.698) and for BMI < 30, ≥ 30 and < 40 and ≥ 40 were 82.9%, 81.7% and 90.9% respectively. Regression analysis showed no affect between BMI or SSD regarding SFR. Conclusion Ureteroscopy should be considered as a first-line of treatment for renal/proximal stones in obese and morbid obese patients. URS may be preferable to SWL in obese patients independently of the SSD, BMI or the location of proximal stones.

Purpose To report the surgical technique, procedural outcomes, and feasibility of simultaneous bilateral Video Endoscopic Inguinal Lymphadenectomy (VEIL) in the management of patients with indication for inguinal lymphadenectomy. Surgical Technique: VEIL was applied in all patients using the oncological landmarks (the adductor longus muscle medially, the sartorius muscle laterally and the inguinal ligament superiorly). A 1.5 cm incision was made 2 cm distally to the lower vertex of the femoral triangle. A second incision was made 2 cm proximally and 6 cm medially. Two 10 mm Hasson trocars were inserted in these incisions and the working space was insufflated with CO2 at 5-15 mmHg. The final trocar was placed 2 cm proximally and 6 cm laterally from the first port. Results: A total of 5 VEIL procedures in 3 patients were performed. Two patients underwent simultaneous bilateral VEIL while another underwent simultaneous bilateral surgery with VEIL on the right and open lymphadenectomy on the left side due to an enlarged node. All laparoscopic procedures were successfully performed without conversion and maintained the oncological templates. One lymphocele occurred in the patient who underwent the open procedure. None of the patients presented with skin necrosis after the procedure. Mean number of nodes retrieved was 6 from each side and 2 patients presented with positive inguinal nodes. After one year of follow-up no recurrences were observed. Conclusion: Simultaneous lymphadenectomy procedures are feasible. Improvement in operative and anesthesia time could decrease the morbidity associated with inguinal lymphadenectomy while maintaining the oncological principles.

INTRODUCTION: The objective of our study is to present the first Brazilian cryoablation experience in the treatment of low and intermediate risk localized prostate cancer using 3rd generation cryoablation and real-time biplanar transrectal ultrasonography. MATERIALS AND METHODS: Ten Brazilian patients underwent primary cryoablation for localized prostate cancer between October 2010 and June 2011. All patients consented for whole gland primary cryotherapy. The procedures were performed by 3rd generation cryoablation with the Cryocare System® (Endocare, Irvine, California). Preoperative data collection included patient demographics along with prostate gland size, Gleason score, serum prostate specific antigen, and erectile function status. Operative and post-operative assessment involved estimated blood loss, operative time, complications, serum PSA level, erectile function status, urinary incontinence, biochemical disease free survival (BDFS), and follow-up time. RESULTS: All patients in the study successfully underwent whole gland cryoablation. The mean of: age, prostate size, PSA level, and Gleason score, was 66.2 years old; 40.7g; 7.8ng/mL; and 6 respectively. All patients were classified as low or moderate D'Amico risk (5 low and 5 moderate). Erectile dysfunction was present in 50% of patients. The estimated blood loss was minimal, operative time was 46.1 minutes. All patients that developed erectile dysfunction post-treatment responded to oral or intracavernosal medications with early penile rehabilitation. All patients maintained urinary continence by the end of a 10 months evaluation period and none had biochemical relapse within the mean follow-up of 13 months (7-15 months). CONCLUSION: Our initial experience shows that cryoablation is a minimally invasive option for the treatment of localized prostate cancer. Short term data seems to be promising but longer follow-up is necessary to verify oncological and functional results.

INTRODUCTION: We present the initial experience of a novel surgical chair for laparoscopic pelvic surgery, the ETHOS TM (Bridge City Surgical, Portland, OR). MATERIALS AND METHODS: The ETHOS chair has an adjustable saddle height that ranges from 0.89 to 1.22 m high, an overall width of 0.89 m, and a depth of 0.97 m. The open straddle is 0.53 m and fits most OR tables. We performed 7 pelvic laparoscopy cases with the 1st generation ETHOS TM platform including 2 laparoscopic ureteral reimplantations, 5 laparoscopic pelvic lymphadenectomies for staging prostate cancer in which one case involved a laparoscopic radical retropubic prostatectomy, performed by 2 different surgeons. RESULTS: All 7 pelvic laparoscopic procedures were successful with the ETHOS TM chair. No conversion to open surgery was necessary. Survey done by surgeons after the procedures revealed minimal stress on back or upper extremities by the surgeons from these operations even when surgery was longer than 120 minutes. Conversely, the surgical assistants still had issues with their positions since they were on either sides of the patient stressing their positions during the procedure. CONCLUSION:The ETHOS chair system allows the surgeon to operate seated in comfortable position with ergonomic chest, arms, and back supports. These supports minimize surgeon fatigue and discomfort during pelvic laparoscopic procedures even when these procedures are longer than 120 minutes without consequence to the patient safety or detrimental effects to the surgical team.

Many organisms respond to anthropogenic environmental change through shifts in their phenology. In plants, flowering is largely driven by temperature, and therefore affected by climate change. However, on smaller scales climatic conditions are also influenced by other factors, including habitat structure. A group of plants with a particularly distinct phenology are the understory herbs in temperate European forests. In these forests, management alters tree species composition (often replacing deciduous with coniferous species) and homogenizes stand structure, and as a consequence changes light conditions and microclimate. Forest management should thus also affect the phenology of understory herbs. To test this, we recorded the flowering phenology of 16 early‐flowering herbs on 100 forest plots varying in management intensity, from near‐natural to intensely managed forests, in central and southern Germany. We found that in forest stands with a high management intensity, such as Norway spruce plantations, the plants flowered on average about 2 weeks later than in unmanaged forests. This was largely because management also affected microclimate (e.g., spring temperatures of 5.9°C in managed coniferous, 6.7 in managed deciduous, and 7.0°C in unmanaged deciduous plots), which in turn affected phenology, with plants flowering later on colder and moister forest stands (+4.5 d per −1°C and 2.7 d per 10% humidity increase). Among forest characteristics, the percentage of conifers had the greatest influence on microclimate, but also the age, overall crown projection area, structural complexity and spatial distribution of the forest stands. Our study indicates that forest management alters plant phenology, with potential far‐reaching consequences for the ecology and evolution of understorey communities. More generally, our study demonstrates that besides climate change other drivers of environmental change, too, can influence the phenology of organisms. [ABSTRACT FROM AUTHOR]

Urban lawns provide space for recreation in cities, and they are an important part of urban green infrastructures. However, most lawns are intensively managed. As only few plant species can survive frequent mowing, urban lawns typically harbor only a limited number of plant species. To improve the biodiversity of urban lawns, it is often suggested to reduce the mowing frequency. Here, we studied the plant diversity of urban grasslands that have recently undergone management changes from mowing every few weeks to mowing only once or twice per season and compared them to intensively managed lawns. Within six years after the management changes, the grasslands with reduced mowing frequency hosted 30% more plant species than intensively managed lawns, and they were more heterogeneous both within and between grasslands. Additionally, the species composition of less frequently mown grasslands shifted from common mowing-tolerant lawn species to typical meadow species. Our study thus shows that the reduction of mowing is a simple and effective tool for increasing the biodiversity in urban grasslands. [ABSTRACT FROM AUTHOR]

Targeted therapy development in head and neck squamous cell carcinoma (HNSCC) is challenging given the rarity of activating mutations. Additionally, HNSCC incidence is increasing related to human papillomavirus (HPV). We sought to develop an in vivo model derived from patients reflecting the evolving HNSCC epidemiologic landscape, and use it to identify new therapies. Primary and relapsed tumors from HNSCC patients, both HPV+ and HPV−, were implanted on mice, giving rise to 25 strains. Resulting xenografts were characterized by detecting key mutations, measuring protein expression by IHC and gene expression/pathway analysis by mRNA‐sequencing. Drug efficacy studies were run with representative xenografts using the approved drug cetuximab as well as the new PI3K inhibitor PX‐866. Tumors maintained their original morphology, genetic profiles and drug susceptibilities through serial passaging. The genetic makeup of these tumors was consistent with known frequencies of TP53, PI3KCA, NOTCH1 and NOTCH2 mutations. Because the EGFR inhibitor cetuximab is a standard HNSCC therapy, we tested its efficacy and observed a wide spectrum of efficacy. Cetuximab‐resistant strains had higher PI3K/Akt pathway gene expression and protein activation than cetuximab‐sensitive strains. The PI3K inhibitor PX‐866 had anti‐tumor efficacy in HNSCC models with PIK3CA alterations. Finally, PI3K inhibition was effective in two cases with NOTCH1 inactivating mutations. In summary, we have developed an HNSCC model covering its clinical spectrum whose major genetic alterations and susceptibility to anticancer agents represent contemporary HNSCC. This model enables to prospectively test therapeutic‐oriented hypotheses leading to personalized medicine. Highlights: This HNSCC xenograft model includes all clinical subtypes by location and HPV status.Mutation profile is representative of seminal sequencing reports (Including NOTCH).Morphology, gene expression and drug sensitivity are stable over generations.Cases with PI3KCA alterations were sensitive to the novel PI3K inhibitor PX‐866.PI3K inhibition was effective in two cases harboring NOTCH1 mutations. [ABSTRACT FROM AUTHOR]

Summary: The protein kinase Bβ (Akt2) pathway is known to mediate insulin-stimulated glucose transport through increasing glucose transporter GLUT4 translocation from intracellular stores to the plasma membrane (PM). Combining quantitative phosphoproteomics with RNAi-based functional analyses, we show that a previously uncharacterized 138 kDa C2 domain-containing phosphoprotein (CDP138) is a substrate for Akt2, and is required for optimal insulin-stimulated glucose transport, GLUT4 translocation, and fusion of GLUT4 vesicles with the PM in live adipocytes. The purified C2 domain is capable of binding Ca2+ and lipid membranes. CDP138 mutants lacking the Ca2+-binding sites in the C2 domain or Akt2 phosphorylation site S197 inhibit insulin-stimulated GLUT4 insertion into the PM, a rate-limiting step of GLUT4 translocation. Interestingly, CDP138 is dynamically associated with the PM and GLUT4-containing vesicles in response to insulin stimulation. Together, these results suggest that CDP138 is a key molecule linking the Akt2 pathway to the regulation of GLUT4 vesicle-PM fusion. [Copyright &y& Elsevier]